Highlights from Recent Cancer Literature
Journal: Cancer Research (2019)

Neutrophils can both promote and inhibit cancer in different settings. In cases of cancer promotion, neutrophils take on suppressive characteristics. Patel and colleagues reveal an additional mechanism wherein nonimmunosuppressive neutrophils promote cancer in a stage-specific fashion. Utilizing genetically engineered and transplantable mouse models of cancer, they demonstrated that early stage cancers (but not advanced cancers) directed the enhanced spontaneous (e.g. nonchemokine directed) migration of neutrophils from the bone marrow. While the mechanism of increased migratory capacity is undefined, the authors found that migration depended upon increased glycolysis and oxidative phosphorylation in neutrophils, generating ATP that was secreted, and enhanced migration in a paracrine fashion via purinergic receptors. Ultimately, these migratory neutrophils supported seeding of tumor cells in new tissues, thus establishing a mechanism of cancer cell and neutrophil cross-talk that drives cancer progression.Expert Commentary: Cancer stage-specific communication between cancer cells and neutrophils enhances the migration of neutrophils to tissue sites through metabolic mechanisms, potentially supporting the early dissemination of cancer cells.Patel S, Fu S, Mastio J, Dominquez GA, Purohit A, Kossenkov A, et al. Unique pattern of neutrophil migration and function during tumor progression. Nat Immunol 2018;19:1236–47.Although the tumor suppressive function of hypophosphorylated RB through its inhibition of the E2F proteins is well accepted, a tumor suppressive role for hyperphosphorylated RB has not been previously reported. Jin and colleagues describe a tumor suppressive function of hyperphosphorylated Rb in promoting tumor immunity through the inhibition of NF-κB–induced upregulation of PD-L1. They demonstrated that CDK4/6-dependent hyperphosphorylated RB inhibits NF-κB activity through binding of its p65 subunit. This interaction required phosphorylation of RB at the S249/T252 residues. Thus, RB deletion or CDK4/6 inhibition led to NF-κB activation and increased PD-L1. Phosphorylated RB was also required for radiation-induced PD-L1 expression and immune tolerance. RB phosphorylation-mimetic peptides could prevent this therapy-induced upregulation of PD-L1 and restore tumor immunity.Expert Commentary: This study suggests that inhibiting NF-κB activation with RB phosphorylation mimetics may potentially prevent immune tolerance seen with current therapies.Jin X, Ding D, Yan Y, Li H, Wang B, Ma L, et al. Phosphorylated RB promotes cancer immunity by inhibiting NF-κB activation and PD-L1 expression. Molecular Cell; Published online December 3, 2018; doi: 10.1016/j.molcel.2018.10.034.IFNγ is a potent cytokine known to modulate tumor immunity and tumoricidal effects. Strikingly, serum IFNγ levels become elevated after radiotherapy in patients with prostate cancer. In this study Lo and colleagues demonstrate that IFNγ is capable of inducing epithelial-mesenchymal transition (EMT) in prostate cancer, leading to cancer invasiveness via interferon-induced tetratricopeptide repeat 5 (IFIT5)–mediated turnover of tumor suppressor miRNAs. Depletion of IFIT5 decreased IFNγ-induced cell invasiveness in vitro and lung metastasis in vivo. IFIT5 was highly elevated in high-grade prostate cancer and its expression correlated inversely with these suppressive miRNAs. Evidence was provided for a unique IFIT5-XRN1 complex involved in the turnover of specific tumor suppressive miRNAs, providing an underlying mechanism for IFNγ-induced EMT in prostate cancer.Expert Commentary: This study uncovers a unique prometastatic role of the IFNγ pathway that occurs through a new mechanism of action, turnover of specific tumor- suppressive miRNAs, which raises concerns about clinical applications promoting IFNγ production.Lo UG, Pong RC, Yang D, Gandee L, Hernandez E, Dang A, et al. IFNγ-induced IFIT5 promotes epithelial-to-mesenchymal transition in prostate cancer via microRNA processing. Cancer Research; Published first November 30, 2018; doi: 10.1158/0008-5472.CAN-18-2207.Conventional chemotherapy for patients with acute myeloid leukemia (AML) often kills the majority of dividing tumor cells, but spares at least some disease-initiating leukemia stem cell (LSC) populations. Jones and colleagues analyzed the metabolome of human AML stem cells to elucidate properties relevant to therapeutic intervention. They found that amino acid uptake, steady-state levels, and catabolism were all elevated in LSCs. In addition, LSCs isolated from patients with primary AML were specifically dependent on amino acid metabolism for oxidative phosphorylation and survival. Pharmacological inhibition of amino acid metabolism resulted in reduced oxidative phosphorylation and cell death. In contrast, LSCs obtained from relapsed patients were independent of amino acid metabolism, compensating through increased fatty acid metabolism.Expert Commentary: These data suggest that drugs that target metabolic vulnerabilities of LSCs could be clinically relevant for patients with AML.Jones CL, Stevens BM, D'Alessandro A, Reisz JA, Culp-Hill R, Nemkov T, et al. Inhibition of amino acid metabolism selectively targets human leukemia stem cells. Cancer Cell 2018;34:724–40.CDK12 mutations have been identified in cancers characterized by BRCAness signatures. Dubbury and colleagues elucidate mechanisms by which CDK12 mutations in BRCAness tumors affect DNA damage response genes. CDK12 regulates transcription elongation and is reportedly involved in splicing, cleavage, and polyadenylation, with depletion abrogating the expression of genes involved in homologous recombination (HR) repair. The authors generated Cdk12 knockouts in mouse embryonic stem cells and confirmed defective HR repair in these cells. Contrary to published results, no splicing defects were seen. However, previously published 3′-end sequencing data from mES cells confirmed global increases in intronic polyadenylation (IPA). To determine relevance to human cancer, they analyzed public RNA-seq datasets from serous ovarian and prostate adenocarcinoma with CDK12 loss-of-function mutations to demonstrate increased IPA usage within BRCAness genes. These effects were also validated using the CDK12/13 inhibitor THZ531.Expert Commentary: This study demonstrates the role of CDK12 in suppressing premature termination through increased IPA usage. Although the majority of the data were obtained in mES cells, their confirmation in public data sets suggests that these could be extrapolated to cancers with CDK12 loss-of-function mutations.Dubbury SJ, Boutz PL, Sharp PA. CDK12 regulates DNA repair genes by suppressing intronic polyadenylation. Nature 2018;564:141–5.Circulating tumor cells (CTC) seed metastases at distant sites, although molecular mechanisms involved are not fully understood. CTC clusters were identified in the vasculature of human and mouse patient-derived xenograft models with metastatic breast cancer. Liu and colleagues show that these clusters have enhanced cancer stem cell properties compared with single cells and, furthermore, that clustered CTCs were enriched for the stem cell marker CD44. CD44 directed homophilic cell-cell interactions and was required for clustering of the CTCs and formation of lung metastases. Mechanistically, CD44 binds to p21 protein-activated kinase 2 (PAK2), which contributes to CD44-mediated cell clustering via activation of downstream signaling pathways.Expert Commentary: This study sheds light on how subsets of CTCs drive metastatic spread through increased stemness. The association of CD44+ CTC clusters with lower overall survival in women with breast cancer highlights the importance of CD44-mediated signaling pathways in this process.Liu X, Taftaf, Kawaguchi M, Chang YF, Chen W, Entenberg D, et al. Homophilic CD44 interactions mediate tumor cell aggregation and polyclonal metastasis in patient-derived breast cancer models. Cancer Discovery; Published first December 17 2018; doi: 10.1158/2159-8290.CD-18-0065.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.